1. Technical Field of the Invention
The present invention relates to inhibiting the expression of VEGF by administration of retinoids, in particular anti-AP-1 (Activator Protein-1) retinoids. This invention also relates to the retinoid treatment of disease states manifesting an overexpression of VEGF, in particular psoriasis, Kaposi's syndrome, bullous dermatoses, tumors, metastases, angiomas, eczema, urticaria, cutaneous hypersensitivity type IV, rheumatoid arthritis, and contact allergies.
2. Description of the Prior Art
VEGF, or "Vascular Endothelial Growth Factor," is a 34-36 kDa homodimeric glycoprotein whose sequence reflects an approximately 20% identity with the A and B chains of PDGF (Tischer et al., J. Biol. Chem., 266, 11947-11954 (1991)). The additional DNA sequence of VEGF codes for a signal peptide enabling it to be secreted in opposition to FGF (Fibroblast Growth Factor), which does not contain such a sequence in the structure of its gene. Because the major production sites and the action sites are different, VEGF acts principally in a paracrine mode. The presence of VEGF has been discovered in both numerous tumors and healthy tissue (D. L. Senger et al., Cancer Metastasis Rev., 12, 303-324 (1993)).
In healthy skin, the expression of VEGF may be increased following an injury (L. F. Brown et al., J. Exp. Med., 176, 1375-1379 (1992)). The overexpression of VEGF has also been determined in numerous skin diseases associated with vascular hyperproliferation and/or to vascular changes, as in psoriasis patches (M. Detmar et al., J. Exp. Med., 180, 1141-1146 (1994)), in Kaposi's syndrome (K. Weindel et al., Biochem. Biophys. Res. Commun., 183, 1167-74 (1992)), and in bullous dermatoses (L. F. Brown et al., J. Invest. Dermatol., 104, 744-749 (1995)).
It is widely known that all-trans retinoic acid affects cell differentiation and/or proliferation by interacting with nuclear receptors, or sRAR (Retinoic Acid Receptors) contained in the cell nucleus. 9-cis retinoic acid also interacts with Retinoic X Receptors (sRXR). Numerous synthetic analogs exhibit biological activity similar to that of all-trans retinoic acid or 9-cis-retinoic acid. These compounds are generally designated "retinoids." Included among the retinoids are, more specifically, RAR agonists, which interact with the sRAR receptors; these include etretinate and adapalene. To date, there are three known subclasses of RAR receptors, termed .alpha.-RAR, .beta.-RAR, and .gamma.-RAR. After fixation of a ligand (i.e., all-trans retinoic acid), these receptors interact with the region promoting genes regulated by retinoic acid in specific response elements (RARE).
Certain analogs may become fixed and may activate a subclass of RAR receptor (.alpha., .beta., or .gamma.). Finally, other analogs elicit no specific selective activity with respect to these various receptors. In this regard, for example, all-trans retinoic acid activates the sRAR (sRAR specific agonist ligand) belonging to all subclasses.
Numerous dermatological diseases and/or disorders may entail poor regulation of the sRAR receptors. These diseases and/or disorders most often exhibit an inflammatory, allergic, and/or immunological component. Retinoic acid, and, retinoids such as etretinate and adapalene, are drug species used to treat acne. Retinoic acid has also been described as a therapeutic active agent for treating the signs of skin aging, whether chronological or photoinduced (U.S. Pat. No. 4,888,342).
Certain retinoids have been described as effective for regulating the expression of genes, such as keratins (M. Tomic-Canic et al., J. Biol. Chem., 271, 1416-1423 (1996)) or for altering PDGF activity in psoriatic fibroblasts (F. Raynaud et al., J. Invest. Dermatol., 96, 111-115 (1991)). And certain retinoids have also been demonstrated to exhibit anti-AP-1 activity, namely, they inhibit AP-1 activity (WO-95/33,745). To date, no effect elicited by retinoids on VEGF expression has been reported in the literature (see, for example, Harada et al., J. Clin. Invest., 93, 2490-2496 (1993)).